Kaposi's sarcoma-associated virus (KSHV) is the etiological agent of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). KS is a highly angiogenic tumor that is driven by KSHV-infected endothelial cells, and KS lesions express high levels of cytokines and angiogenic growth factors. We have found that latent KSHV infection dramatically alters angiogenesis, migration, and survival of endothelial cells. Latent KSHV infection of endothelial cells results in the upregulation of multiple cytokines and chemokines. We hypothesize that the upregulated cytokines and chemokines play important roles in driving angiogenesis and cell proliferation of KSHV-infected cells, and we propose to determine the mechanism by which these factors regulate cell growth, survival, and angiogenesis. We will also determine how KSHV infection affects cell migration. Finally, we have identified cellular and viral proteins that modulate the ubiquitin pathway. Hence, we propose to determine how these factors alter cellular ubiquitination pathways, to promote cell migration and survival of the infected cell. In summary, we propose to analyze the biological pathways that are altered upon KSHV infection of endothelial cells in order to understand the mechanism of KSHV-mediated oncogenesis. We hypothesize that the modulation of cell migration, angiogenesis and anti-apoptotic pathways by KSHV promotes tumorigenesis and contributes to the pathogenesis associated with KSHV infection. Thus, the proposed studies will provide significant and biologically relevant insights into KSHV biology, and will also identify new targets for future therapies against KSHV-associated cancers.